Use of 2,5-Dihydroxybenzene Derivatives for Treating Actinic Keratosis

ABSTRACT

The present invention relates to the use of a 2,5-dihydroxybenzene derivative represented by Formula (I) or a pharmaceutically acceptable salt, solvate, isomer, or prodrug thereof for the therapeutic and/or phrophylactic treatment of, inter alia, actinic keratosis.

RELATED APPLICATIONS

This application is a continuation-in-part of U.S. Ser. No. 11/506,469,which is a national stage filing under 35 U.S.C. § 371 of InternationalApplication Number PCT/ES05/70017, filed Feb. 16, 2005, which claims thebenefit of priority under 35 U.S.C. § 119 of ES Application NumberP200400371, filed Feb. 17, 2004. In addition, this application claimsthe benefit of priority under 35 U.S.C. § 119 of ES Application No.P200602219, filed Aug. 16, 2006 and of ES Application No. P200701857,filed Jul. 2, 2007. The foregoing applications, and all documents citedtherein, are hereby incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to the use of 2,5-dihydroxybenzenederivatives to manufacture medicaments useful to prevent and/or treatskin aging due to exposure to ultraviolet B rays (UVB), or to exposureto sun rays in general, to treat pathologies associated to said skinphotoaging such as skin wrinkles or actinic keratosis, pigmentation andhyperpigmentation of the skin, as well as to treat obesity due toexcessive adipogenesis, hirsutism, hypertricosis and viral warts.

BACKGROUND OF THE INVENTION

Chronic exposure to ultraviolet B rays (UVB: 290-320 nm wavelength), orsolar rays, in general (comprising, among other wavelengths, that of UVBradiation) produces skin aging (photoaging) due to the accumulation ofDNA damage and on the structural proteins of the skin, evidencing in theform of fine wrinkles, laxity with loss of skin elasticity, elastosis,yellowish staining with localizad areas of melanin hyperpigmentation(solar, actinic or senile lentigo). Besides, skin photoaging isassociated with the appearance of comedoes that are more evident in the“cutis romboidalis” at the rear part of the neck. In the histologicaltest, an epidermic atrophy and degenerative changes in elastic fibers ofthe dermis may be observed (Pearse A D, Gaskell S A, Marks R. J InvestDermatol 1987; 88 83-87; Berton T R, Mitchell D L, Fischer S M,Looniskar M F. J Invest Dermatol 1997; 109: 340-347). Furthermore,chronic exposure to UVB rays is a risk factor for the appearance ofbenign lesions, such as seborrheic keratosis, and premalignant lesionssuch as actinic keratosis (Kripke M L. Cancer Res 1994; 54: 6102-6105).Currently, there is no effective treatment for skin photoaging (DermatolSurg. Special Issue: Cosmeceuticals. Invited editors: Draelos Z D, BrodyH J. 2005).

On the other hand, the hair follicle is the functional unit for hairelongation. Hirsutism is a clinical condition in which there in anexcessive hair growth with an androgenic-type pattern (face, thorax,areolas, linea alba, lower part of the back, buttocks, limbs andexternal genitals) produced by an increase in the androgenic activity.Hypertricosis is a condition in which there is an excessive hair growthin areas sensitive and non-sensitive to androgens.

Obesity is a disease produced when the energy intake exceeds andproduces an excess of adipose tissue. This process is regulated by thecontrol on the intake, on the energy expenditure and efficiency and onthe adipogenesis). (Gregoire F M. Exp Biol Med, 2001, 226: 997-1002;Palou A et al. Eur J Nutr, 2000, 39: 127-144). Prevention and/ortreatment of obesity is a very important factor to reduce morbidity andmortality rates associated to cardiovascular disorders and to type 2diabetes, which represent a high health and social cost inindustrialized countries. Currently, there is no effective treatment forobesity. The effective therapies to treat obesity should interfere withthe development of adipose tissue. To increase the adipose tissue mass,it is essential that preadipocytes are differentiated in a matureadipocyte phenotype. Besides morphological changes, the differentiationprocess of preadipocyte into adipocyte is accompanied by metabolicprocesses such as the capacity of storing energy in the form oftriglycerides (McDougald O A, Lane M D. Annu Rev Biochem, 1995, 345-373;Spiegelman B M, Flier J S. Cell 1996, 87: 377-389). Therefore, thepharmacological inhibition of the differentiation of preadipocytes intoadipocytes represents a therapeutic strategy to treat obesity.

There is a need to find alternative treatments to the current ones forskin photoaging, hirsutism, or obesity; both from the aesthetic andtherapeutic points of view, based on the use of active principles.

SUMMARY OF THE INVENTION

Surprisingly, the inventors have found that 2,5-dihydroxybenzenederivatives, the pharmaceutically acceptable salts and solvates thereof,as well as isomers and prodrugs thereof are useful to prevent and/ortherapeutically treat skin aging due to exposure to ultraviolet rays B(UVB), or to exposure to sun rays in general, to treat pathologiesassociated with said skin photoaging such as skin wrinkles, actinickeratosis, skin pigmentation and hyperpigmentation, as well to treathirsutism and hypertricosis, obesity due to excessive adipogenesis, andto treat viral warts.

In certain embodiments, the invention provides a method for thetreatment and/or prophylaxis of actinic keratosis, comprisingadministering to a subject in need thereof, an effective amount of a2,5-dihydroxybenzene derivative represented by Formula (I) or apharmaceutically acceptable salt, solvate, isomer, or prodrug thereof,wherein the compound of Formula (I) is:

wherein:

-   -   R₁ is —(CH₂)_(a)Y or —CH═CH—(CH₂)_(p)Y;    -   Y is —SO₃H, —SO₃ ⁻.X⁺, —SO₃R₃, —PO₃H, —PO₃—.X⁺, —PO₃R₃, —CO₂H,        —CO₂ ⁻.X⁺ or —CO₂R₃;    -   X⁺ is an organic cation or an inorganic cation, such that the        general charge of the compound of Formula (I) is neutral;    -   R₉ and R_(9′) are independently selected from —OH and —OR₂,        wherein when R₉ and R_(9′) are both —OR₂, then said R₉ and        R_(9′) can be the same or different;    -   R₂ is a substituted or unsubstituted alkyl group, a substituted        or unsubstituted aryl group, a substituted or unsubstituted        alkylsulfonyl group, a substituted or unsubstituted arylsulfonyl        group, a substituted or unsubstituted alkylcarbonyl group or a        substituted or unsubstituted arylcarbonyl group;    -   R₃ is a substituted or unsubstituted alkyl group or a        substituted or unsubstituted aryl group;    -   a is a number selected from 0, 1, 2, 3, 4, 5 and 6; and    -   p is a number selected from 0, 1, 2, 3, 4, 5 and 6.

In certain embodiments, Y is selected from —SO₃H, —SO₃ ⁻.X⁺, —SO₃R₃,—CO₂H, —CO₂ ⁻.X⁺ and —CO₂R₃. In other embodiments, at least one of R₉and R_(9′) are, independently, a substituted or unsubstitutedalkylsulfonyloxy group, a substituted or unsubstituted arylsulfonyloxygroup, a substituted or unsubstituted alkylcarbonyloxy group or asubstituted or unsubstituted arylcarbonyloxy group. In yet otherembodiments, R₂ is selected from methylcarbonyl, phenylsulfonyl,4-methylphenylsulfonyl, benzylsulfonyl, benzyl and phenyl.

In certain embodiments, the compound of Formula (I) is selected from thegroup consisting of: 2,5-dihydroxybenzenesulfonic acid (Dobesilate),5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;2-(acetyloxy)-5-hydroxybenzenesulfonic acid;5-(acetyloxy)-2-hydroxybenzenesulfonic acid;2,5-bis(acetyloxy)benzenesulfonic acid;2-(benzyloxy)-5-hydroxybenzenesulfonic acid;5-(benzyloxy)-2-hydroxybenzenesulfonic acid;2,5-bis(benzyloxy)benzenesulfonic acid; 2,5-dihydroxybenzenehomosulfonic acid (homodobesilate);5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;2-(acetyloxy)-5-hydroxybenzenehomosulfonic acid;5-(acetyloxy)-2-hydroxybenzenehomosulfonic acid;2,5-bis(acetyloxy)benzenehomosulfonic acid;2-(benzyloxy)-5-hydroxybenzenehomosulfonic acid;5-(benzyloxy)-2-hydroxybenzenehomosulfonic acid;2,5-bis(benzyloxy)benzenehomosulfonic acid; 2,5-dihydroxybenzoic acid(gentisic acid), 5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzoicacid; 2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzoic acid;2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzoic acid;2-(acetyloxy)-5-hydroxybenzoic acid; 5-(acetyloxy)-2-hydroxybenzoicacid; 2,5-bis(acetyloxy)benzoic acid; 2-(benzyloxy)-5-hydroxybenzoicacid; 5-(benzyloxy)-2-hydroxybenzoic acid; 2,5-bis(benzyloxy)benzoicacid; 2,5-dihydroxyhomobenzoic acid (homogentisic acid);5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid;2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid;2,5-bis{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid;2-(acetyloxy)-5-hydroxyhomobenzoic acid;5-(acetyloxy)-2-hydroxyhomobenzoic acid; 2,5-bis(acetyloxy)homobenzoicacid; 2-(benzyloxy)-5-hydroxyhomobenzoic acid;5-(benzyloxy)-2-hydroxyhomobenzoic acid; 2,5-bis(benzyloxy) homobenzoicacid; 3-(2,5-dihydroxyphenyl)-2-propenoic acid (2,5-dihydroxycinnamicacid); 3-(5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoicacid; 3-(2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoicacid; 3-(2,5-bis{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic acid;3-(2-(acetyloxy)-5-hydroxyphenyl)-2-propenioc acid;3-(5-(acetyloxy)-2-hydroxyphenyl)-2-propenoic acid;3-(2,5-bis(acetyloxy)phenyl)-2-propenoic acid;3-(2-(benzyloxy)-5-hydroxyphenyl)-2-propenoic acid;3-(5-(benzyloxy)-2-hydroxyphenyl)-2-propenoic acid;3-(2,5-bis(benzyloxy)phenyl)-2-propenoic acid; and pharmaceuticallyacceptable salts, solvates and prodrugs thereof.

In certain embodiments, the compound of Formula (I) comprises an esterat position 1.

In some embodiments, the compound of Formula (I) is selected from:2-(acetyloxy)-5-hydroxybenzenesulfonic acid;5-(acetyloxy)-2-hydroxybenzenesulfonic acid and2,5-bis(acetyloxy)benzenesulfonic acid.

In yet other embodiments, the compound of Formula (I) is selected fromthe group consisting of: calcium 2,5-dihydroxybenzenesulfonate (calciumDobesilate); potassium 2,5-dihydroxybenzenesulfonate (potassiumDobesilate); magnesium 2,5-dihydroxybenzenesulfonate (magnesiumDobesilate); diethylamine 2,5-dihydroxybenzenesulfonate (Ethamsylate);

In a particular embodiment, the compound of Formula (I) is calcium2,5-dihydroxybenzenesulfonate (calcium Dobesilate).

In another embodiment, the compound of Formula (I) is potassium2,5-dihydroxybenzenesulfonate (potassium Dobesilate).

In certain embodiments, the invention provides a method for thetreatment or prophylaxis of actinic keratosis, wherein the actinickeratosis is selected from the group consisting of: hypertrophic,atrophic, bowenoid, and acantholythic keratosis.

Advantageously, a compound of Formula (I) is administered topically. Incertain embodiments, the compound of Formula (I) is administered orally,buccally, transdermally, by inhalation, rectally, intravaginally, orotically.

In yet other embodiments, the invention provides a method for thetreatment or prophylaxis of actinic keratosis further comprisingadministration of at least one additional therapeutic agent in additionto a compound of Formula (I).

Examples of suitable additional therapeutic agents include imiquimod,diclofenac, glycidic acid, trichloroacetic acid, colchicine, T4endonuclease, 5-fluorouracil, isotretinoin, acitretin, cidofoir,5-aminolevulinic acid, methyl aminolevulinate, hypericin,chemotherapeutic agent, a corticosteroid, an antibiotic, an analgesic,an immunomodulator, an immunosuppressant, an anti-angiogenic (includinganti-VEGF, anti-FGF, anti-EGF and anti-HGF), a leukotriene modifier, anaminosalicylate, an anesthetic, a non-steroidal anti-inflammatory, amodifier of a solubilized interleukin receptor, a cytotoxic, aninhibitor of a tyrosine-kinase receptor, a protein kinase C inhibitor,and combinations of two or more thereof.

In certain embodiments, the invention provides a method for thetreatment or prophylaxis of actinic keratosis comprising administrationof a compound of Formula (I) and further comprising at least onecoadjuvant therapy selected from the group consisting of: photodynamictherapy, cryotherapy, curettage, and surgery.

In certain embodiments, the invention provides for administration of acompound of Formula (I) for the treatment and/or prophylaxis of actinickeratosis, wherein the compound is administered at least once per week.In other embodiments, the compound is administered at least once per dayor at least twice per day.

In certain embodiments, a compound of Formula (I) is present in apharmaceutical composition in an amount of at least about 1% w/w. Inother embodiments, the compound is present in a pharmaceuticalcomposition in an amount of at least about 2.5% w/w, at least about 5%w/w, at least about 10% w/w, or at least about 15% w/w.

In yet other embodiments, a compound of Formula (I) is administered overa period of at least about one week. In certain embodiments, thecompound is administered over a period of at least about four weeks.

These and other aspects of the present invention are described in detailherein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Appearance of aged skin before treatment (A) and after topicaltreatment during three months with a cream containing 5% of2,5-dihydroxybenzenesulfonic acid (B). The arrows indicate the same areaof actinic lentigo before and after treatment.

FIG. 2. The topical treatment with a cream containing 5%2,5-dihydroxybenzenesulfonic acid (twice a day for 11 days) on humanskin (basal conditions shown in FIG. 2A) produces a reduction in theseborrheic keratosis (big circle) as well as in the viral warts (smallcircle), as shown in FIG. 2B.

FIG. 3. Appearance of a patient's facial seborrheic keratosis beforebeing treated (A) and after topical treatment of the affected skin areawith an emulsion containing 2.5% 2,5-dihydroxybenzenesulfonic acid for 4weeks (B). There is a reduction of the seborrheic keratosis.

FIG. 4. Development of actinic keratosis in the scalp of a patientbefore being treated (A, a), after topical treatment of the affectedskin area with an emulsion containing 2.5% 2,5-dihydroxybenzenesulfonicacid for 2 weeks (B, b) and after this 4-week-treatment (C, c). There isa reduction of the actinic keratosis after two weeks of treatment, and amore noticeable lightening of the lesion after 4 weeks of treatment.

FIG. 5. Appearance of a different lesion of actinic keratosis in thesame patient as in FIG. 4, before being treated (A, a) and after topicaltreatment of the affected skin area with an emulsion containing 2.5%2,5-dihydroxybenzenesulfonic acid for 4 weeks (B, b). In this lesion,there is also a clear recovery as a result of the treatment.

FIG. 6. Appearance of a lesion of actinic keratosis in the ear of apatient before being treated (A), after 12 days of topical treatment ofthe affected skin area with a cream containing 5%2,5-dihydroxybenzenesulfonic (B) and after 15 days with this treatment(C). There is a reduction of the actinic keratosis after 12 days oftreatment, and the lesion was cleared after 15 days of treatment.

FIG. 7. Appearance of a lesion of actinic keratosis in the nose of apatient before being treated (A), and after 30 days of topical treatmentof the affected skin area with a cream containing 5%2,5-dihydroxybenzenesulfonate (B). There is a reduction of the actinickeratosis after 30 days of treatment. Circle delimitates the treatedarea.

FIG. 8. Appearance of skin before treatment (A) and after topicaltreatment for 2 months with a cream containing 5% of2,5-dihydroxybenzensulfonic acid (B). In image A, pilosity is moreabundant than in image B.

FIG. 9. Reversal of solar lentigos after treatment for two weeks withcream containing 5% 2,5-dihydroxybenzenesulfonic acid (DHBS). A, beforetreatment. B, after treatment.

FIG. 10. Photograph A corresponds to a control culture where most of thecells are adipocytes containing triglyceride deposits. Photo B shows aculture treated with 2,5-dihydroxybenzenesulfonic acid (DHBS). Most ofthese cells treated with DHBS exhibit a non-differentiated(pre-adipocytes) appearance with scarce accumulation of triglycerides inthe cytoplasm.

FIG. 11. Represents a histogram corresponding to the quantification oftriglycerides (spectrophotometrically detected by the Oil Red Oabsorbance) in three control cultures and in three cultures ofpreadipocytes treated with 2,5-dihydroxybenzenesulfonic acid (DHBS, 25μM). Ordinates: absorbance at 510 nm. The accumulation of triglyceridesin the cells treated with DHBS (black bar) is significantly smaller thanin the untreated cells (control) (white bar), *** p<0.001.

FIG. 12. Inhibition of the differentiation between pre-adipocytes andthe adipogenesis by the gentisic acid (2,5-dihydroxybenzoate; 50 μM).Photograph A is the control and photograph B is the result of thetreatment with gentisic acid for two weeks.

FIG. 13. Inhibition of the differentiation between pre-adipocytes andthe adipogenesis by the gentisic acid (2,5-dihydroxybenzoate; 50 μM).The axis Y represents the percentage of absorbance at 510 nm. Theaccumulation of triglycerides in the cells treated with2,5-dihydroxybenzoate (stripped bar) is significantly smaller than inthe untreated cells (control) (white bar), * p<0.05.

FIG. 14. Inhibition of the proliferation of preadipocytes by2,5-dihydroxybenzenesulfonic acid (DHBS). DHBS was administered or not(control) after seeding subcutaneous fat pre-adipocytes belonging to arabbit in 24 well plates (10⁴ per well) until they were fixed 72 hourslater. Data is expressed as the mean ±SEM of the percentage ofabsorbance at 595 nm obtained in control cultures, which is proportionalto the number of cells stained with crystal violet. Data were obtainedfrom 3 cultures for each treatment. The white bar represents thecontrol, whereas the black bars represent the percentage in presence ofDHBS (10 to 100 μM). * indicates p<0.05, *** p<0.001 regarding controlthrough a one-factor analysis of variance (ANOVA) of a factor followedby a Student-Newmann-Keuls post-analysis.

FIG. 15. Inhibition of the proliferation of pre-adipocytes by2-acetoxy-5-hydroxybenzenesulfonic acid (2A-5HBS). 2A-5HBS wasadministered or not (control) after seeding subcutaneous fatpre-adipocytes belonging to a rabbit in 24 well plates (10⁴ per well)until they were fixed 72 hours later. Data is expressed as the mean ±SEMof the percentage of absorbance at 595 nm obtained in control cultures,which is proportional to the number of cells stained with crystalviolet. Data were obtained from 3 cultures for each treatment. The whitebar represents the control, whereas the black bars represent thepercentage in presence of 2A-5HBS (10 a 500 μM). *** indicates p<0.001regarding control through a one-factor analysis of variance (ANOVA)followed by a Student-Newmann-Keuls post-analysis.

FIG. 16. Inhibition of the mitogenesis induced by fibroblast growthfactor-1 in Balb/c 3T3 fibroblast quiescent cultures by calcium2-acetoxy-5-hydroxybenzenesulfonate (2A-5HBS) and potassium2,5-dihydroxybenzenesulfonate (DHBS).

FIG. 17. Inhibition of the mitogenesis induced by fibroblast growthfactor-1 in Balb/c 3T3 fibroblast quiescent cultures by potassium5-acetoxy-2-hydroxybenzenesulfonate (5A-2HBS) and potassium2,5-dihydroxybenzenesulfonate (DHBS).

FIG. 18. Inhibition of the mitogenesis induced by fibroblast growthfactor-1 in Balb/c 3T3 fibroblast quiescent cultures by potassium2,5-diacetoxybenzene sulfonate (DABS) and potassium 2,5-dihydroxybenzenesulfonate (DHBS).

FIG. 19. Shows the effect of the treatment with potassium5-acetoxy-2-hydroxybenzenesulfonate (5-mono acetylated dobesilate;5A-2HBS) and the potassium 2-acetoxy-5-hydroxybenzenesulfonate (2-monoacetylated dobesilate; 2A-5HBS) on the proliferation of mouse C6 gliomacells. 5A-2HBS and 2° A.-5HBS were administered or not (control) afterseeding C6 cells in 24 well plates (10⁴ per well) until they were fixed48 hours later. Data is expressed as the mean ±SEM of the percentage ofabsorbance at 595 nm obtained in control cultures, which is proportionalto the number of cells stained with crystal violet. Data were obtainedfrom 3 cultures for each treatment and 6 control cultures. The white barrepresents the value of the control cells, whereas the black bar showsthe value in the presence of 5A-2HBS (500 μM), and the stripped barshows the value in the presence of 2A-5HBS (500 μM). *** indicatesp<0.001 regarding control through a one-factor analysis of variance(ANOVA) followed by a Student-Newmann-Keuls post-analysis.

FIG. 20. Co-crystallized potassium 5-acetoxy-2-hydroxybenzenesulfonicacid with fibroblast growth factor-1. The electron density of thecompound, contoured at 1σ (panel C), enables the localization andrecognition of the compound orientation regarding the protein (panels Aand B), as well as the confirmation that the compound maintains theacetoxyl group in position 2 when it binds to the protein. The compoundis located at a site very close to the site that, as described, isoccupied by the 2,5-dihydroxybenzenesulfonic acid, which aromatic ringforms a cation-π bond with the N^(ε) group of lysine 132, marked inpanel A as reference. Panel B shows, in the form of a mesh, the Van derWaals volume of 2-acetoxy-5-hydroxybenzenesulfonic acid, overlapped toits representation in the form of rods. In panels A and B, the proteinsurface is colored according to its electrostatic potential (light grey:negative charge; dark grey: positive charge; white: lack of charge).

FIG. 21. Co-crystallized potassium 5-acetoxy-2-hydroxybenzenesulfonicacid with fibroblast growth factor-1. The electron density of thecompound, contoured at 1σ (panel C), enables the localization andrecognition of the compound orientation regarding the protein (panels Aand B) as well as the confirmation that the compound maintains theacetoxyl group in position 5 when it binds to the protein. The compoundis located at a site very close to the site that, as described, isoccupied by the 2,5-dihydroxybenzenesulfonic acid, which aromatic ringforms a cation-π bond with the N^(ε) group of lysine 132, marked inpanel A as reference. Panel B shows, in the form of a mesh, the Van derWaals volume of 2-acetoxy-5-hydroxybenzenesulfonic acid, overlapped toits representation in the form of rods. In panels A and B, the proteinsurface is colored according to its electrostatic potential (light grey:negative charge; dark grey: positive charge; white: lack of charge).

FIG. 22. Co-crystallized 2,5-diacetoxybenzenesulfonic acid withfibroblast growth factor-1. The electron density of the compound,contoured at 1σ (panel C), enables the localization and recognition ofthe compound orientation regarding the protein (panels A and B) as wellas the confirmation that the compound maintains the acetoxyl groups inpositions 2 and 5 when it binds to the protein. The compound is locatedat a site very close to the site that, as described, is occupied by the2,5-dihydroxybenzenesulfonic acid, which aromatic ring forms a cation-πbond with the N^(ε) group of lysine 132, marked in panel A as reference.Panel B represents, in the form of a mesh, the Van der Waals volume of2,5-diacetoxybenzenesulfonic acid, overlapped to its representation inthe form of rods. In panels A and B, the protein surface is coloredaccording to its electrostatic potential (light grey: negative charge;dark grey: positive charge; white: lack of charge).

DETAILED DESCRIPTION OF THE INVENTION

The definitions of the terms and the chemical groups comprised in theformulas herein are as follows:

The term “patient” refers to animals, preferably mammals, and morepreferably humans, and includes males and females, children and adults.

The expression “effective amount” refers to the amount of compoundand/or composition effective to achieve the desired purpose.

The terms “treat” or “treatment” refer to the prophylactic use ofcompounds or compositions of the present invention to avoid the symptomsof the disease or condition, or the therapeutical use to improve anexisting condition.

“Alkyl” refers to a linear or branched chain hydrocarbon radicalcomprising carbon atoms and hydrogen, with no unsaturations, with one totwelve, preferably one to eight, more preferably one to six carbonatoms, bound to the rest of the molecule by a single bond, for example,methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, etc.

“Alkenyl” refers to a linear or branched chain hydrocarbon radicalcomprising carbon atoms and hydrogen atoms, containing at least oneunsaturation, with two to twelve, preferably two to eight, morepreferably two to six carbon atoms, bound to the rest of the molecule bya single bond.

“Cycloalkyl” refers to a saturated carbocyclic ring having between threeand eight, preferably three to six carbon atoms. They may exhibit abridged structure. Suitable cycloalkyl groups include, but are notlimited to, cycloalkyl groups such as cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl.

“Alkynyl” refers to a linear or branched chain hydrocarbon radicalcomprising carbon atoms and hydrogen, containing at least one triplecarbon-carbon bond, whether conjugated or not, with two to twelve,preferably two to eight, more preferably two to six carbon atoms, boundto the rest of the molecule by a single bond such as —CCH, —CH₂CCH,—CCCH₃, —CH₂CCCH₃.

“Aryl” refers to an aromatic hydrocabon radical containing from six toten carbon atoms such as phenyl or naphthyl.

“Aralkyl” refers to an aryl group bound to the rest of the molecule byan alkyl group such as benzyl and phenetyl.

“Heterocycle” refers to a stable 3 to 15-membered ring comprised ofcarbon atoms and between one and five heteroatoms selected from thegroup consisting of nitrogen, oxygen and sulfur, preferably a 4 to8-membered ring with two, three or four heteroatoms, more preferably a 5or 6-membered ring with one, two or three heteroatoms. For the purposeof the present invention, the heterocycle may be a monocyclic, bicyclicor tryciclic ring system that may include fused ring systems; bridgedstructures; and the nitrogen, carbon or sulfur atoms in the heterocyclicradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized; and the heterocyclic radical may be partially or completelysaturated or it may be aromatic. Examples of such heterocycles include,but are not limited to, azepines, benzimidazole, benzothiazole, furan,isothiazole, imidazole, indole, piperidine, piperazine, quinoline,thiadiazol, tetrahydrofuran.

Unless otherwise specified, the alkyl, cycloalkyl, alkenyl, alkynyl,aryl, aralkyl and heterocycle radicals may be optionally substituted byone, two or three substituents such as halo, alkyl, alkenyl, alkynyl,aryl, cycloalkyl, hydroxy, alkoxy, sulfoxy, O-Benzyl, O-Benzoyl,carboxyl, alkylcarboxyl, arylcarboxyl, alkylcarbonyl, arylcarbonyl,cyano, carbonyl, acyl, alkoxycarbonyl, amino, alkylamino, dialkylamino,arylamino, diarylamino, alkylarylamino, imino, alkylsulphinyl, amidyl,carbamoyl, sulfonamido, nitro, nitrite, nitrate, thionitrate andcarboxamido.

The term “alkoxycarbonyl” refers to a compound having the formula—C(═O)O—, where the C-terminal is bound to the molecule and theO-terminal is bound to a carbon atom to form an ester function. Saidcarbon atom may be part of an alkyl, alkenyl, cycloalkyl, alkynyl, aryl,aralkyl or heterocyclic group.

The term “alkoxycarbonylalkyl” refers to a compound of the previouslydefined formula —C(═O)O—, wherein the C-terminal binds to a moleculethrough an alkyl group. The terms “aryloxy-arylalkoxy- oralkylaryloxy-carbonylalkyl” will be understood similarly to“alkoxycarbonylalkyl”.

The term “arylalkyl” refers to an aryl radical, as defined herein, boundto an alkyl radical, as defined herein. The exemplary arylalkyl groupsinclude benzyl, phenylethyl, 4-hydroxybenzyl, 3-fluorobenzyl,2-fluorophenylethyl and the like.

The term “alkylaryl” refers to an alkyl group, as defined herein, towhich an aryl group is bound, as defined herein. The exemplary alkylarylgroups include benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl,fluorophenylethyl, and the like.

The term “alkylsulfonyl” refers to a R₅₀—S(O)₂—, wherein R₅₀ is a loweralkyl group, as defined herein.

The term “arylsulfonyl” refers to a R₅₅—S(O)₂—, wherein R55 is an arylgroup, as defined herein.

The term “alkylsulphinyl” refers to a R₅₅—S(O)₂—, wherein R55 is an arylgroup, as defined herein.

The term “arylsulphinyl” refers to a R₅₅—S(O)₂—, wherein R₅₅ is an arylgroup, as defined herein.

The term “sulfonamide” refers to a —S(O)₂—N(R₅₁)(R₅₇), wherein R₅₁ andR₅₇ are each independently a hydrogen atom, an alkyl group, an arylgroup, heterocycle, as defined herein, or else R₅₁ and R₅₇ together forma heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group,as defined herein.

The term “alkylsulfonamide” refers to a sulfonamido group, as definedherein, bound to an alkyl group, as defined herein.

The term “arylsulfonamide” refers to a sulfonamido group, as definedherein, bound to an aryl group, as defined herein.

The term “alkylcarbonyl” refers to a R₅₂—C(O)₂—, wherein R₅₂ is an alkylgroup, as defined herein.

The term “arylcarbonyl” refers to the R₅₅—S(O)₂— radical, wherein R55 isan aryl group, as defined herein.

The term “carboxamide” refers to a —C(O)N(R₅₂)(R₅₈) radical, wherein R₅₂and R₅₈ are each independently a hydrogen atom, an alkyl group, an arylgroup or an heterocyclic group, as defined herein or else R₅₁ and R₅₇together form an heterocyclic ring, a cycloalkyl group, or a bridgedcycloalkyl group, as defined herein.

The term “carboxylic ester” refers to —C(O)OR₅₉, wherein R₅₉ is an alkylgroup an aryl group or an heterocyclic group, as defined herein.

The term “alcoxyalkyl” refers to an alcoxy group, as defined herein,bound to an alkyl group, as defined herein. Examples of alcoxyalkylgroups are methoxymethyl, methoxyethyl, isopropoximethyl and the like.

The term “amine” refers to any organic compound containing at least onebasic nitrogen atom.

The term “organic cation” refers to a positively charged organic ion.The exemplary organic cations include ammonium cations unsubstituted orsubstituted with alkyl, primary, secondary o tertiary amines,alkylamines, arylamines, cyclic amines, N,N′-dibenzylethylenediamine,and the like.

The term “inorganic cation” refers to a positively charged metal ion.The exemplary inorganic cations include Group I metal cations such assodium, potassium, magnesium, calcium and the like.

The term “prodrug” refers to compounds that rapidly convert in vivo intopharmacologically active compounds. Prodrug design is generally studiedin Hardma et al. (eds.), Goodman and Gilman's The Pharmacological Basisof Therapeutics, 9th ed., pages 11-16 (1996). A thorough study ispresented in Higuchi et al., Prodrugs as Novel Delivery Systems, vol.14, ASCD Symposium Series, and in Roche (ed.), Bioreversible Carriers inDrug Design, American Pharmaceutical Association and Pergamon Press(1987).

The compounds of the invention having one or more asymmetric carbonatoms may exist as optically pure enantiomers, pure diastereomers,mixtures of enantiomers, mixtures of diastereomers, racemic mixtures ofenantiomers, diastereomeric racemates or mixtures of diastereomericracemates. It should be clearly understood that the inventioncontemplates and includes these isomers and mixtures thereof within itsscope.

The term “ester derivative of a compound of formula (I)” refers to thecompound of formula (I) wherein at least one of R₉ and R_(9′) is anester group. For example, the ester derivative of 2,5-dihydroxybenzenesulfonic acid or dobesilate ester derivative refers to the compound2,5-dihydroxybenzene sulfonic acid (dobesilate) wherein at least one ofthe hydroxyl groups has been esterified.

The term “ester of a compound of formula (I)” refers to an ester of thesulfonic or carboxylic acid group at position 1. For example, the esterof 2,5-dihydroxybenzensulfonic acid or ester of dobesilate refers to anester of the sulfonic acid group at position 1.

The term “topical” refers to the administration of a compound byapplying it on the body surface and includes, but is not limited to,transdermal administration and administration through the mucosa.

The term “transdermal” refers to the delivery of a compound that entersinto the bloodstream through the skin.

The expression “through the mucosa” refers to the delivery of a compoundthat enters into the bloodstream through the mucous tissue.

The term “parenteral” refers to the administration of a compound bymeans of a subcutaneous, intravenous, intramuscular, intracardiac,intradermic, intraperitoneal, intrathecal or intrasternal injection; andalso includes local or systemic infusion techniques.

The expression “penetration enhancement” or “permeation enhancement”refers to the increase in the permeability of the skin or mucous tissueto a pharmacologically active compound selected in such a way that itincreases the penetration rate through the skin or mucous tissue.

“Excipients” or “vehicles” refers to the vehicle materials suitable forcompound administration and include any such material known in the artsuch as, for example, any liquid, gel, solvent, liquid diluent,solubilizer, or the like, which is non-toxic and which does not showharmful interaction with any component of the composition.

The expression “sustained release” refers to the release of an activecompound and/or composition such that the blood levels of the activecompound are maintained within a desirable therapeutic range over aperiod of time. The sustained release formulation may be prepared usingany conventional known method by a skilled in the art in order to obtainthe desired release characteristics.

“Viral warts” refers to benign growths of the skin or mucosa.

“Actinic keratosis” refers to dry, squamous lesions with gritty textureformed in the external layer of the skin after years of exposure toultraviolet light, such as solar rays.

“Seborrheic keratosis” refers to non-cancerous growth of the externallayer of the skin.

“Obesity” refers to an excess accumulation of adipose tissue.

“Excessive adipogenesis” refers to an excess in the formation of adiposetissue.

“Hirsutism” refers to an excessive growth of hair in women in androgenicareas.

“Hypertricosis” is a general growth of body hair, not limited to certainareas.

“Skin photoaging” refers to an alteration in the skin caused by solarexposure.

“Skin wrinkles” refers to wrinkles produced on the skin due to cutaneousphotoaging.

The term “therapeutic agent” includes any active agent that can be usedto treat or prevent a disease described herein. “Therapeutic agents”include but are not limited to immunomodulatory treatments, such as atacrolimus ointment or a pimecrolimus cream and the like; topicalcorticosteroids (cream, unguents, ointments or gels) or systemiccorticosteroids; topical or systemic immunosupressants, such as, forexample, cyclosporine, metrotrexate, azathioprine, and the like;phototherapy; emollients such as for example, white petrolatum, eucerin,urea cream, mineral oil, aluminum acetate, and the like; barrier creams,sucha as, for example, zinc oxide paste, and the like; moisturizingagents, such as, for example, menthol, camphor, and the like; localanesthetics, such as, for example, lidocaine, and the like; topicalcorticoids, such as, for example, triamcinolone acetate, and the like;systemic corticoids, such as, for example, prednisone, and the like;antihistamines, such as, for example, diphenhydramine, hydroxyzine, andthe like; podophylline resin, locally applied; cantharin, only combinedwith podophylline; salicylic acid, locally applied; imiquimod;bleomycin; exfoliating agents, such as, for example, alpha hydroxy acids(glycolic acid, salicylic acid, lactic acid), trichloroacetic, phenols(carbolic acid, croton oil, and the like; diclofenac gel;5-fluorouracyl, bleaching agents and photoprotectors, and the like. Atherapeutic agent includes pharmaceutically acceptable salts thereof,prodrugs and pharmaceutical derivatives thereof.

In a first aspect, the present invention relates to the use of acompound of a 2,5-dihydroxybenzene represented by Formula (I) or apharmaceutically acceptable salt or solvate, isomer or prodrug thereofto prepare a medicament for the cosmetic, therapeutic and/orprophylactic treatment of actinic keratosis, obesity due to excessiveadipogenesis, hirsutism, hypertricosis, viral warts, pigmentation and/orhyperpigmentation of the skin wherein the compound of the Formula (I)is:

wherein:

-   -   R₁ is —(CH₂)_(a)Y or —CH═CH—(CH₂)_(p)Y;    -   Y is —SO₃H, —SO₃ ⁻.X⁺, —SO₃R₃, —PO₃H, —PO₃—.X⁺, —PO₃R₃, —CO₂H,        —CO₂ ⁻.X⁺ or —CO₂R₃;    -   X⁺ is an organic cation or an inorganic cation, such that the        general charge of the compound of Formula (I) is neutral;    -   R₉ and R_(9′) are independently selected from —OH and —OR₂;        wherein when R₉ and R_(9′) are both —OR₂, then said R₉ and        R_(9′) can be the same or different;    -   R₂ is a substituted or unsubstituted alkyl group, a substituted        or unsubstituted aryl group, a substituted or unsubstituted        arylalkyl group, a substituted or unsubstituted alkylsulfonyl        group, a substituted or unsubstituted arylsulfonyl group, a        substituted or unsubstituted alkylarylsulfonyl group, a        substituted or unsubstituted arylalkysulfonyl group, a        substituted or unsubstituted aryloxyalkyl group, a substituted        or unsubstituted alkylcarbonyl group or an arylcarbonyl group, a        carboxyl group, a substituted or unsubstituted alkoxycarbonyl        group, a substituted or unsubstituted carboxyalkyl group, in        particular —CH₂—COOH, or a substituted or unsubstituted        alkoxy-aryloxy-arylalkoxy- or alkylaryloxy-carbonylalkyl, in        particular —CH₂—COOR₃;    -   R₃ is a substituted or unsubstituted alkyl group, a substituted        or unsubstituted aryl group, a substituted or unsubstituted        arylalkyl group, or a substituted or unsubstituted alkylaryl        group;    -   a is number selected from 0, 1, 2, 3, 4, 5 and 6; and    -   p is number selected from 0, 1, 2, 3, 4, 5 and 6.

In a particular embodiment, the 2,5-dihydroxybenzene derivatives of theinvention or any of the pharmaceutically acceptable salts thereof arethose that are represented by Formula (I) comprising Dobesilate,Homodobesilate, dobesilate esters derivatives and the pharmaceuticallyacceptable salts thereof for the treatment of actinic keratosis, obesitydue to excessive adipogenesis, hirsutism, hypertricosis and viral warts.

Particularly, the present invention comprises 2,5-dihydroxybenzenederivatives of the invention or any of the pharmaceutically acceptablesalts thereof, represented by Formula (I) comprising gentisic acid,homogentisic acid, gentisic acid ester derivatives, homogentisic acidester derivatives, 2,5-dihydroxycinnamic acid, 2,5-dihydroxycinnamicacid ester derivatives, homodobesilate ester derivatives, and thepharmaceutically acceptable salts thereof, for the treatment of actinickeratosis, obesity due excessive adipogenesis, hirsutism, hypertricosisand viral warts.

In a particular embodiment of the invention 2,5-dihydroxybenzenicderivatives of formula (I) are used to preprare a medicament for thecosmetic, therapeutic and/or prophylactic treatment of actinickeratosis. More particularly, the actinic keratosis is selected from thegroup consisiting of hypertrophic, atrophic, bowenoid, and acantholythickeratosis.

In this case, when the medicament is for the cosmetic, therapeuticand/or prophylactic treatment of actinic keratosis, 2,5-dihydroxybenzenederivatives of the invention may be used optionally and jointly with atleast one of the following therapeutic agents: imiquimod, diclofenac,glycidic acid, trichloroacetic acid, colchicine, T4 endonuclease,5-fluorouracil, isotretinoin, acitretin, cidofoir, 5-aminolevulinicacid, methyl aminolevulinate, hypericin, chemotherapeutic agent, acorticosteroid, an antibiotic, an analgesic, an immunomodulator, animmunosuppressant, an anti-angiogenic (including anti-VEGF, anti-FGF,anti-EGF and anti-HGF), a leukotriene modifier, an aminosalicylate, ananesthetic, a non-steroidal anti-inflammatory, a therapy of thesolubilized interleukin receptor, a cytotoxic, inhibitors oftyrosin-kinase receptors, protein kinase C inhibitors, and combinationsof two or more thereof.

In a particular embodiment, the therapeutic agent is selected from thegroup consisting of 5-aminolevulinic, methyl aminolevulinate andhypericine.

In another particular embodiment the therapeutic and/or prophylactictreatment of actinic keratosis further comprises photodynamic therapy,cryotherapy, curettage and surgery as a coadjuvant therapy.

In another particular embodiment, 2,5-dihydroxybenzenic derivatives offormula (I) are used to preprare a medicament for the cosmetic,therapeutic and/or prophylactic treatment of obesity, hirsutism,hypertricosis and viral warts.

In this particular case, when the medicament is for the cosmetic,therapeutic and/or prophylactic treatment of obesity, hirsutism,hypertricosis and viral warts, 2,5-dihydroxybenzenie derivatives of theinvention may be used optionally and jointly with at least one of thefollowing therapeutic agents: imiquimod, diclofenac, glycidic acid,trichloroacetic acid, colchicine, T4 endonuclease, 5-fluorouracil,isotretinoin, acitretin, statins, any other hypolypidemic agent andcidofoir.

Another aspect of the invention is that 2,5-dihydroxybenzene derivativesmay be optionally used combined with each other. In this manner and asan example, it is possible to combine the dobesilate with thehomogentisic, or the gentisic with the homogentisic, or a dobesilateester derivative with the homogenisic, and the like in the same or in adifferent ratio. Said combinations may be in the same formulation or informulations that would be used sequentially.

The X⁺ cation in the compound of Formula (I) may be any physiologicallyacceptable cation known in the art, that includes but is not limited tothose described in P. Heinrich Stahl, Camille G. Wermuth (eds.),“Handbook of Pharmaceutical Salts Properties, Selections and Use”,Verlag Helvetica Chimica Acta, Zurich, Switzerland, Wiley-VCH, Weinheim,Germany, 2002.

The X⁺ cation is typically selected in such a way that the generalcharge of Formula (I) is neutral.

In a particular embodiment of the invention Y is selected from —SO₃H,—SO₃ ⁻.X⁺, —SO₃R₃, —CO₂H, —CO₂ ⁻.X⁺ and —CO₂R₃.

In another particular embodiment, at least one of R₉ and R_(9′) are,independently, a substituted or unsubstituted alkylsulfonyloxy group, asubstituted or unsubstituted arylsulfonyloxy group, a substituted orunsubstituted alkylcarbonyloxy group or a substituted or unsubstitutedarylcarbonyloxy group.

In another particular embodiment, R₂ is selected from methylcarbonyl,phenylsulfonyl, 4-methylphenylsulfonyl, benzylsulfonyl, benzyl andphenyl.

In another particular embodiment of the invention, R₂ is selected fromacetyl (—C(O)CH₃), tosyl (—SO₂—C₆H₄—CH₃) or p-chlorophenoxyisobutyryl(—C(O)—C(CH₃)₂—O—C6H₄Cl).

In another particular embodiment of the invention, R₃ is selected frommethyl, ethyl, isopropyl or C₆H₅—, more particularly form methyl andethyl.

In a preferred embodiment of the invention, the inorganic cation issodium, potassium, lithium, calcium, or magnesium.

In another preferred embodiment of the invention, the organic cation is[NH_(4-p)R_(p)]⁺: wherein p is an integer between 0 and 4 and R is analkyl group having one to six carbon atoms such as, for example, methyl,ethyl, n-propyl, i-propyl, t-butyl or n-pentyl.

In another preferred embodiment of the invention, the organic cation isthe diethylamine [H₂N⁺(C₂H₅)₂], piperazine or pyridine group.

In another preferred embodiment of the invention, the compound ofFormula (I) and acceptable salts thereof are:

wherein:n is a number selected from 1 and 2;m is a number selected from 1 and 2; and

X, R₂ and R₃ are as defined in the present invention.

In a more preferred embodiment of the invention, the compound of FormulaI is:

-   2,5-dihydroxybenzenesulfonic acid (Dobesilate),-   5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;-   2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;-   2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;-   2-(acetyloxy)-5-hydroxybenzenesulfonic acid;-   5-(acetyloxy)-2-hydroxybenzenesulfonic acid;-   2,5-bis(acetyloxy)benzenesulfonic acid;-   2-(benzyloxy)-5-hydroxybenzenesulfonic acid;-   5-(benzyloxy)-2-hydroxybenzenesulfonic acid;-   2,5-bis(benzyloxy)benzenesulfonic acid;-   2,5-dihydroxybenzene homosulfonic acid (homodobesilate)-   5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;-   2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;-   2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;-   2-(acetyloxy)-5-hydroxybenzenehomosulfonic acid;-   5-(acetyloxy)-2-hydroxybenzenehomosulfonic acid;-   2,5-bis(acetyloxy)benzenehomosulfonic acid;-   2-(benzyloxy)-5-hydroxybenzenehomosulfonic acid;-   5-(benzyloxy)-2-hydroxybenzenehomosulfonic acid;-   2,5-bis(benzyloxy)benzenehomosulfonic acid;-   2,5-dihydroxybenzoic acid (gentisic acid),-   5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzoic acid;-   2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzoic acid;-   2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzoic acid;-   2-(acetyloxy)-5-hydroxybenzoic acid;-   5-(acetyloxy)-2-hydroxybenzoic acid;-   2,5-bis(acetyloxy)benzoic acid;-   2-(benzyloxy)-5-hydroxybenzoic acid;-   5-(benzyloxy)-2-hydroxybenzoic acid;-   2,5-bis(benzyloxy)benzoic acid;-   2,5-dihydroxyhomobenzoic acid (homogentisic acid),-   5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid;-   2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid;-   2,5-bis{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid;-   2-(acetyloxy)-5-hydroxyhomobenzoic acid;-   5-(acetyloxy)-2-hydroxyhomobenzoic acid;-   2,5-bis(acetyloxy)homobenzoic acid;-   2-(benzyloxy)-5-hydroxyhomobenzoic acid;-   5-(benzyloxy)-2-hydroxyhomobenzoic acid;-   2,5-bis(benzyloxy)homobenzoic acid;-   3-(2,5-dihydroxyphenyl)-2-propenoic acid (2,5-dihydroxycinnamic    acid);-   3-(5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic    acid;-   3-(2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic    acid;-   3-(2,5-bis{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic acid;-   3-(2-(acetyloxy)-5-hydroxyphenyl)-2-propenoic acid;-   3-(5-(acetyloxy)-2-hydroxyphenyl)-2-propenoic acid;-   3-(2,5-bis(acetyloxy)phenyl)-2-propenoic acid;-   3-(2-(benzyloxy)-5-hydroxyphenyl)-2-propenoic acid;-   3-(5-(benzyloxy)-2-hydroxyphenyl)-2-propenoic acid;-   3-(2,5-bis(benzyloxy)phenyl)-2-propenoic acid;    and pharmaceutically acceptable salts, solvates and prodrugs    thereof.

In a more preferred embodiment, the compound of Formula (I) is 2,5dihydroxybenzenesulfonic (Dobesilate) or the ester derivatives orpharmaceutically acceptable salts thereof. Particularly preferred arethe compounds 2-(acetyloxy)-5-hydroxybenzenesulfonic acid;5-(acetyloxy)-2-hydroxybenzenesulfonic acid and2,5-bis(acetyloxy)benzenesulfonic acid.

In another preferred embodiment, the compound of formula (I) is selectedfrom the group consisting of:

-   calcium 2,5-dihydroxybenzenesulfonate (calcium Dobesilate);-   potassium 2,5-dihydroxybenzenesulfonate (potassium Dobesilate);-   magnesium 2,5-dihydroxybenzenesulfonate (magnesium Dobesilate);-   diethylamine 2,5-dihydroxybenzenesulfonate (Ethamsylate).

Particularly preferred are calcium 2,5-dihydroxybenzenesulfonate(calcium dobesilate) and potassium 2,5-dihydroxybenzenesilfonate(potassium dobesilate).

In another preferred embodiment, the compounds of formula (I) are in theform of esters at position 1, in particular methyl and ethyl esters.

The compounds of Formula (I) may be synthesized by one skilled in theart using conventional and commercially available methods. The synthesisof the compounds of Formula (I) is disclosed in, for example, U.S. Pat.No. 5,082,941; and “The Merck Index” 13th. edition, Merck & Co., R.Railway, N.J., USA, 2001; U.S. Pat. Nos. 5,082,841, 4,814,110, 4,613,332and 4,115,648; the disclosures which are incorporated herein byreference in their entirety.

Compounds of Formula (I) also may be in the form of solvates,particularly in the form of hydrates. The preparation of the compoundsof Formula (I), as well as the solvates thereof may be carried out byone skilled in the art using conventional methods and commerciallyavailable reagents.

Even as it has been previously mentioned in one of the preferredembodiments with respect to the definition of X⁺ cation, the scope ofthe present invention encompasses any salt thereof, especially anypharmaceutically acceptable salt of the compound. The phrase“pharmaceutically acceptable salts” includes metal salts or the additionsalts that may be used in pharmaceutical forms. For example, thepharmaceutically acceptable salts of the compounds provided herein maybe acid addition salts, base addition salts or metal salts and they maybe synthesized from the parenteral compounds containing a base or acidresidue using conventional chemical processes. Generally, those saltsare prepared, for example, by the reaction of free base or acid forms ofthese compounds with a stoichiometric amount of the appropriate base oracid in water or in an organic solvent, or in a mixture of both.Generally, non aqueous mediums such as ether, ethyl acetate, ethanol,isopropanol or acetonitrile are preferred. The examples of acid additionsalts include addition salts of mineral acids such as, for example,hydrochloride, bromhydrate, iodide hydrate, sulfate, nitrate, phosphate,addition salts of organic acids such as, for example, acetate, maleate,fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate,methanesulfonate and p-toluenesulfonate. The examples of alkali additionsalts include inorganic salts such as, for example, ammonium salts andorganic alkaline salts such as, for example, diethylamine,ethylenediamine, ethanolamine, N,N-dialkylenethanolamine,triethanolamine, glutamine and basic amino acid salts. The examples ofmetal salts include, for example, sodium, potassium, calcium, magnesium,aluminum, and lithium salts.

In some embodiments, the invention provides a composition comprising anester of Formula I, especially an ester of dobesilate, such as2-acetyloxy-5-hydroxybenzenesulfonic acid,5-acetyloxy-2-hydroxybenzenesulfonic acid, or2,5-bis-acetyloxybenzenesulfonic acid. In some embodiments, it will bedesirable to formulate a composition of the invention with an activeagent such as an ester of dobesilate, for example, where the esterdemonstrates greater therapeutic efficacy than the parent compound inthe treatment or prevention of a condition described herein. In otherembodiments, the invention encompasses the use of an ester of dobesilateas a prodrug, for example, to treat a condition described herein,wherein the ester is metabolized to the parent compound in a patient toachieve therapeutic efficacy in the patient.

The phrase “pharmaceutically acceptable” refers to physiologicallytolerable molecular entities and compositions which do not typicallyproduce an allergic or similar adverse reaction, such as gastric upset,dizziness, and the like, when administered to a human. Preferably, asused herein, the term “pharmaceutically acceptable” means that it isapproved by a regulatory agent of the Federal or a state government orlisted in the U.S. Pharmacopeia or other generally recognizedpharmacopoeia as suitable for use in animals, and more particularly, inhumans.

It would be obvious to those skilled in the art that the scope of thepresent invention also encompasses salts that are not pharmaceuticallyacceptable as possible media to obtain pharmaceutically acceptablesalts.

As used herein, the term “solvate” shall refer to any form of the activecompound according to the invention that exhibits another molecule (mostprobably, a polar solvent) bound to it through a non-covalent bond.Examples of solvates include hydrates and alcoholates, preferably, C₁-C₆alcoholates, for example, methanolate.

The pharmaceutically acceptable salts of Formula (I) may be preparedfrom organic or inorganic acids or bases by conventional methods throughthe reaction of the appropriate acid or base with the compound.

A medicament comprising a compound of formula (I) of the invention maybe presented in any suitable form for administration, for example, forsystemic, transdermal, oral, parenteral, buccal, nasal (e.g., byinhalation), topical, rectal, or intravaginal administration; therefore,a medicament of the invention may include the acceptable pharmaceuticalexcipients or vehicles necessary to be formulated in the desired form ofadministration. In a preferred embodiment, the pharmaceuticalcomposition is administered topically.

Thus, in one preferred aspect, the present invention refers to a methodfor the treatment and/or prophylaxis of actinic keratosis, obesity dueto excessive adipogenesis, hirsutism, hypertricosis, viral warts, skinwrinkles, skin pigmentation and/or skin hyperpigmentation in a patientin need of the treatment and it comprises the administration to thepatient of an effective amount of the described compounds and/orcompositions of Formula (I).

In other embodiments, the application of the 2,5-dihydroxybenzenecompounds represented by Formula (I) may be made independently or, in apreferred aspect, simultaneously with the use of equivalent or differentmixes of other 2,5-dihydroxybenzene compounds represented by Formula (I)(including pharmaceutically acceptable salts and esters) and thesecompounds may be in the same formulation or in independent formulationsthat would be simultaneously or sequentially administered.

In another aspect, the present invention refers to a cosmetic productcomprising 2,5-dihydroxybenzene derivatives or any of thepharmaceutically acceptable salts thereof represented by Formula (I).

In an embodiment, the present invention refers to a cosmetic productthat comprises 2,5-dihydroxybenzene derivatives or any of thepharmaceutically acceptable salts thereof represented by Formula (I)characterized in that the compound of Formula (I) is2,5-dihydroxybenzenesulfonic acid (dobesilate) or pharmaceuticallyacceptable salts or esters thereof.

In another embodiment, the present invention refers to a cosmeticproduct that comprises 2,5-dihydroxybenzene derivatives or any of thepharmaceutically acceptable salts thereof represented by Formula (I)characterized in that the compound of Formula (I) is2,5-dihydroxybenzoic acid (gentisic acid) or pharmaceutically acceptablesalts or esters thereof.

In another embodiment, the present invention refers to a cosmeticproduct that comprises 2,5-dihydroxybenzene derivatives or any of thepharmaceutically acceptable salts thereof represented by Formula (I)characterized in that the compound of Formula (I) is 2,5-dihydroxyphenylacetic acid (homogentisic acid) or pharmaceutically acceptable salts oresters thereof.

In another embodiment, the present invention refers to a cosmeticproduct that comprises 2,5-dihydroxybenzene derivatives or any of thepharmaceutically acceptable salts thereof represented by Formula (I)characterized in that the compound of Formula (I) is3-(2,5-dihydroxyphenyl)-2-propenoic acid (dihydroxycinnamic acid) orpharmaceutically acceptable salts or esters thereof.

In another embodiment, the present invention refers to a cosmeticproduct that comprises 2,5-dihydroxybenzene derivatives or any of thepharmaceutically acceptable salts thereof represented by Formula (I)characterized in that the compound of Formula (I) is2,5-dihydroxybenzene homosulfonic acid (homodobesilate) orpharmaceutically acceptable salts or esters thereof.

In another embodiment, the present invention refers to a cosmeticproduct characterized in that the compound of Formula (I) is the2,5-dihydroxybenzenesulfonic acid (dobesilate) or the pharmaceuticallyacceptable salts or esters thereof characterized in that it consists ofa formulation for anti-photoaging or photoprotection of the skin.

In another embodiment, the present invention refers to a cosmeticproduct characterized in that the compound of Formula (I) is2,5-dihydroxybenzenesulfonic acid (dobesilate) or the pharmaceuticallyacceptable salts or esters thereof characterized in that it consists ofa formulation for lightening skin hyperpigmentation.

In another embodiment, the present invention refers to a cosmeticproduct characterized in that the compound of Formula (I) is2,5-dihydroxybenzenesulfonic acid (dobesilate) or the pharmaceuticallyacceptable salts or esters thereof characterized in that is consists ofa formulation to treat hirsutism and/or hypertricosis.

In another embodiment, the present invention refers to a cosmeticproduct characterized in that the compound of Formula (I) is the2,5-dihydroxybenzenesulfonic acid (dobesilate) or the pharmaceuticallyacceptable salts or esters thereof characterized in that it consists ofa formulation to treat viral warts and/or actinic keratosis.

In another embodiment, the present invention refers to a cosmeticproduct characterized in that the compound of Formula (I) is the2,5-dihydroxybenzenesulfonic acid (dobesilate) or the pharmaceuticallyacceptable salts or esters thereof characterized in that it consists ofa formulation for the aesthetical treatment of obesity.

In another embodiment, the present invention refers to a cosmeticproduct characterized in that the compound of Formula (I) is the2,5-dihydroxybenzenesulfonic acid (dobesilate) or the pharmaceuticallyacceptable salts or esters thereof characterized in that it consists ofa formulation to be therapeutically used in skin wrinkles.

In another embodiment, the present invention refers to a cosmeticproduct characterized in that the compound of Formula (I) is thegentisic acid or the homogentisic acid or the pharmaceuticallyacceptable salts or esters thereof characterized in that it consists ofa formulation for the aesthetic treatment of obesity due to excessadipogenesis, for the treatment of hirsutism, hypertricosis, viral wartsand actinic keratosis.

In another embodiment, the present invention refers to a cosmeticproduct according to any of the previous aspects characterized in thatit is presented in the form of cream, ointment, unguent, microsomes,bandages, or patches.

In another embodiment, the present invention refers to a cosmeticproduct according to any of the previous aspects characterized in thatit contains an amount of 5% of 2,5-dihydroxybenzene sulfonic acid,potassium salt.

In another embodiment, the present invention refers to a cosmeticproduct according to any of the previous aspects characterized in thatit comprises as excipients: cetyl alcohol (2.5%), stearyl alcohol(2.5%), liquid vaseline (30%), filante vaseline (20%), sorbitanmonooleate (5%) and distilled water (q.s. to 100 g).

In another embodiment, the present invention refers to the use of2,5-dihydroxybenzene derivatives or any of the pharmaceuticallyacceptable esters or salts thereof represented by Formula (I) to preparea formulation intended to be cosmetically used.

In another embodiment, the present invention refers to a method forcosmetic or therapeutic treatment of any of the indications comprised inthe following group: obesity due to excess adipogenesis, hirsutism,hypertricosis, viral warts, and/or actinic keratosis comprising theadministration to a patient of a composition comprising a compound ofFormula (I).

In one embodiment, the present invention refers to the use of2,5-dihydroxybenzene derivatives or any pharmaceutically acceptableesters or salts thereof represented by Formula (I) wherein the compoundof Formula (I) is 2,5-dihydroxybenzensulfonic acid (dobesilate) or thesalts or esters thereof, to prepare a drug or medicine intended for thecosmetic or therapeutic treatment of obesity due to excess adipogenesis,actinic keratosis, to treat hirsutism and hypertricosis and viral warts.

In one embodiment, the present invention refers to the use of2,5-dihydroxybenzene derivatives or any pharmaceutically acceptableesters or salts thereof represented by Formula (I) wherein the compoundof Formula (I) is gentisic acid or the salts or esters thereof, toprepare a drug or medicine intended for the cosmetic or therapeutictreatment of obesity due to excess adipogenesis, actinic keratosis, totreat hirsutism and hypertricosis and viral warts.

In one embodiment, the present invention refers to the use of2,5-dihydroxybenzeneic derivatives or any pharmaceutically acceptableesters or salts thereof represented by Formula (I) wherein the compoundof Formula (I) is 3-(2,5-dihydroxyphenyl)-2-propenoic acid(dihydroxycinnamic acid) or the salts or esters thereof, to prepare adrug or medicine intended for the cosmetic or therapeutic treatment ofobesity due to excess adipogenesis, actinic keratosis, to treathirsutism and hypertricosis and viral warts.

In one embodiment, the present invention refers to the use of2,5-dihydroxybenzene derivatives or any pharmaceutically acceptableesters or salts thereof represented by Formula (I) wherein the compoundof Formula (I) is homodobesilate or the salts or esters thereof, toprepare a drug or medicine intended for the cosmetic or therapeutictreatment of obesity due excess adipogenesis, actinic keratosis, totreat hirsutism and hypertricosis and viral warts.

In another embodiment, the present invention refers to the use of2,5-dihydroxybenzene derivatives or any pharmaceutically acceptableesters or salts thereof represented by Formula (I) wherein the compoundof Formula (I) is 2,5-dihydroxyphenyl acetic acid (homogentisic acid) orthe salts or esters thereof, to prepare a drug or medicine intended forthe cosmetic or therapeutic treatment of obesity due to excessadipogenesis, actinic keratosis, to treat hirsutism and hypertricosis,skin wrinkles, viral warts, and pathologies associated with cutaneousphotoaging, such as, for example, skin pigmentation, skinhyperpigmentation or solar lentigos.

In one embodiment, the present invention refers to a method for cosmetictreatment of any of the indications comprised in the following group:skin wrinkles, hirsutism, hypertricosis, viral warts, actinic keratosisor obesity wherein the compound of Formula (I) is2,5-dihydroxybenzenesulfonic (dobesilate) or the salts or estersthereof.

Similarly, as previously explained in the description, in one aspect,the present invention refers to the use of 2,5-dihydroxybenzenederivatives, the pharmaceutically acceptable esters or salts thereofrepresented by Formula (I) to prepare a drug, medicine or compositionintended for the cosmetic treatment of any of the following diseases:obesity due to excess adipogenesis, actinic keratosis, viral warts,hypertricosis or hirsutism.

In another aspect, the present invention refers to the use of2,5-dihydroxybenzene derivatives represented by Formula (I) wherein thecompound of Formula (I) is 2,5-dihydroxybenzenesulfonic (dobesilate) orthe pharmaceutically acceptable esters or salts thereof to prepare adrug, medicine or composition intended for the cosmetic treatment of anyof the following diseases: skin wrinkles or actinic keratosis.

Another aspect of the present invention refers to a method for cosmetictreatment method of any of the diseases comprised in the followinggroup: obesity due to excess adipogenesis, actinic keratosis, viralwarts, skin wrinkes, hypertricosis or hirsutism comprising theadministration to a patient of a composition comprising Formula (I), orthe pharmaceutically acceptable salts or esters thereof.

Another aspect of the present invention refers to a method fortherapeutic treatment of any of the diseases comprised in the followinggroup: obesity due to excess adipogenesis, actinic keratosis, skinwrinkles, viral warts, hypertricosis, hirsutism, diseases associated toskin photoaging, such as, for example, skin pigmentation, skinhyperpigmentation or solar lentigos consisting in the administration toa patient of a composition comprising Formula (I), or thepharmaceutically acceptable salts or esters thereof.

The duration of treatment will typically depend on the particularcondition, its severity, the condition of the patient, and the like, andwill readily be determined by one of skill in the art. Illustrativecourses of therapy include 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 3.5months, 4 months, 4.5 months, 5 months, 6 months, 9 months, a year, orlonger as needed.

In treating a subject suffering from a disorder described herein,treatment may be continued until at least a 10% improvement is effectedin a symptom associated with the condition. In other embodiments,treatment is continued until the subject in need of such treatmentexperiences an improvement of at least about 20%, at least about 30%, atleast about 40%, preferably at least about 50%, preferably at leastabout 60%, more preferably at least about 70%, more preferably at leastabout 80%, even more preferably 90% or greater in a symptom associatedwith a disorder described herein.

In a particular embodiment of the invention, a compound of formula (I)is administered at least once per week. In other embodiments, a compoundof formula (I) is administered at least once per day. In yet otherembodiments, a compound of formula (I) is administered twice per day. Inanother particular embodiment, a compound of formula (I) is administeredover a period of at least about one week. In other embodiments, acompound of formula (I) is administered over a period of at least aboutfour weeks.

Therapeutic amounts can be empirically determined and will vary with theparticular condition being treated, the subject, the particularformulation components, dosage form, and the like.

In a particular embodiment, a compound of formula (I) is present in apharmaceutical composition in an amount of at least about 1% w/w. Inother embodiments, a compound of formula (I) is present in apharmaceutical composition in an amount of at least about 2.5% w/w, atleast about 5% w/w, at least about 10% w/w, or at least about 15% w/w.

In one aspect of the invention, the inventive 2,5-dihydroxybenzenecompounds of Formula (I) may be administered topically in a formulationcomprising from about 0.001% to about 30% (w/w) of the inventive2,5-dihydroxybenzene compounds: of Formula (I). In a preferred aspect ofthe invention, the inventive 2,5-dihydroxybenzene compounds: of Formula(I) may be administered topically in a formulation comprising from about0.01% to about 20% (w/w) of the inventive 2,5-dihydroxybenzenecompounds: of Formula (I). In another preferred aspect of the invention,the inventive 2,5-dihydroxybenzene compounds: of Formula (I) may beadministered topically in a formulation comprising from about 0.1% toabout 15% (w/w) of the inventive 2,5-dihydroxybenzene compounds: ofFormula (I). In a preferred aspect of the invention, the inventive2,5-dihydroxybenzene compounds: of Formula (I) may be administeredtopically in a formulation comprising from about 0.5% to about 10% (w/w)of the inventive 2,5-dihydroxybenzene compounds: of Formula (I). Inanother preferred aspect of the invention, the inventive2,5-dihydroxybenzene compounds: of Formula (I) may be administeredtopically in a formulation comprising from about 1% to about 5% (w/w) ofthe inventive 2,5-dihydroxybenzene compounds: of Formula (I). In anotherpreferred aspect of the invention, the inventive 2,5-dihydroxybenzenederivatives: of Formula (I) may be administered topically in aformulation comprising from about 2.5% to about 4% (w/w) of theinventive 2,5-dihydroxybenzene compounds: of Formula (I). The topicformulation of the compounds comprised in the inventive2,5-dihydroxybenzene compounds: of Formula (I) may be administered as asingle dose once a day or in multiple doses several times a day. In apreferred aspect of the invention, the topical formulation whichcomprises 30%, 20%, 15%, 10%, 5%, 2.5%, 1%, 0.5%, 0.1% or 0.001% of theinventive 2,5 dihydroxybenzene compounds: of Formula (I), isadministered four times a day. In another preferred aspect of theinvention, the topical formulation which comprises about 30%, 20%, 15%,10%, 5%, 2.5%, 1%, 0.5%, 0.1% or 0.001% of the inventive 2,5dihydroxybenzene compounds: of Formula (I), is administered three timesa day. In another preferred aspect of the invention, the topicalformulation which comprises about 30%, 20%, 15%, 10%, 5%, 2.5%, 1%,0.5%, 0.1% or 0.001% of the inventive 2,5 dihydroxybenzene compounds: ofFormula (I), is administered twice a day. In another preferred aspect ofthe invention, the topical formulation which comprises about 30%, 20%,15%, 10%, 5%, 2.5%, 1%, 0.5%, 0.1% or 0.001% of the inventive 2,5dihydroxybenzene compounds: of Formula (I), is administered once a day.

Topical Compositions

The product of the present invention is useful for topical applicationon the skin. The compositions comprise an effective amount of theinventive compounds: of Formula (I), preferably from about 0.001 to 30%.Furthermore, the composition comprises a pharmaceutical acceptablevehicle. The appropriate vehicles remain in the place of application onthe skin forming a continuous film resistant to water immersion andperspiration. Generally, the vehicle is organic and capable ofcontaining the formulation of the invention in a diluted or dispersedform. Lotions, creams, solutions, gels and solids are the usual physicalforms of the composition.

Topical application means depositing or spreading the compound and thecompositions over the epidermic tissue (including skin and oral,gingival, nasal, etc. tissues).

Lotions

Lotions contain from about 0.001% to about 30% of the inventivecompounds of Formula: (I) from 1% to 25% of an emollient and theappropriate amount of water. Examples of emollients are:

-   -   I. Hydrocarbon waxes and oils such as mineral oils, petrolatum,        paraffin, ceresin, microcrystalline wax, polyethylene and        perhydrosqualene.    -   II. Silicone oils such as dimethylpolysiloxanes,        methylphenylpolysiloxanes and water-soluble and alcohol-soluble        glycol-silicone copolymers.    -   III. Triglycerides, such as animal and vegetable fats and oils.        Examples include, but are not limited to, castor oil, cod liver        oil, corn oil, olive oil, almond oil, palm oil, sesame oil,        cotton seed oil and soybean oil.    -   IV. Acetoglyceride esters, such as acetylated monoglycerides.    -   V. Ethoxylated glycerides, such as ethoxylated glycerol        monostearate.    -   VI. Alkyl esters of fatty acids having 10 to 20 carbon atoms.        Methyl, isopropyl and butyl esters of fatty acids are useful        herein. Examples inclue, but are not limited to, hexyl laurate,        isohexyl laurate, isohexyl palmitate, isopropyl palmitate, decyl        oleate, isodecyl oleate, hexadecyl stearate, decyl stearate,        isopropyl isostearate, diisopropyl adipate, diisohexyl adipate,        dihexyldecyl adipate, diisopropyl sebacate, lauryl lactate,        myristoyl lactate and cetyl lactate.    -   VII. Alkenyl esters of fatty acids having 10 to 20 carbon atoms.        Examples thereof include, but are not limited to, oleyl        myristate, oleyl stearate and oleyl oleate.    -   VIII. Fatty acids having 10 to 20 carbon atoms. Suitable        examples include, but are not limited to, pelargonic, lauric,        myristic, palmitic, stearic, isostearic, hydroxystearic, oleic,        linoleic, ricinoleic, arachidonic, behenic and erucic acids.    -   IX. Fatty alcohols having 10 to 20 carbon atoms. Lauryl,        myristoyl, palmitoyl, stearyl, isostearyl, hydroxystearyl,        oleyl, ricinoleyl, behenyl, erucyl and 2-octyl dodecanol        alcohols are appropriate examples of fatty alcohols.    -   X. Fatty alcohol ethers. Ethoxylated fatty alcohols having 10 to        20 carbon atoms include, but are not limited to, lauryl, cetyl,        stearyl, isostearyl, oleyl and cholesterol alcohols having        attached thereto from 1 to 50 ethylene oxide groups or 1 to 50        propylene oxide groups.    -   XI. Ether-esters, such as fatty acid esters of ethoxylated fatty        alcohols.    -   XII. Lanolin and derivatives. Lanolin, lanolin oil, lanolin wax,        lanolin alcohols, lanolin fatty acids, isopropyl lanolate,        ethoxylated lanolin, ethoxylated lanolin alcohols, ethoxylated        cholesterol, propoxylated lanolin alcohols, acetylated lanolin,        acetylated lanolin alcohols, lanolin alcohols linoleates,        lanolin alcohols ricinoleate, acetate of lanolin alcohols        ricinoleate, hydrogenolysis of lanolin, and liquid or semisolid        lanolin absorption bases are illustrative examples of lanolin        derived emollients.    -   XIII. Polyhydric alcohols and polyether derivatives. Propylene        glycol, dipropylene glycol, polypropylene glycol 2000 and 4000,        polyoxyethylene polypropylene glycols, glycerol, ethoxylated        glycerol, propoxylated glycerol, sorbitol, ethoxylated sorbitol,        hydroxypropyl sorbitol, polyethylene glycol 200-6000, methoxy        polyethylene glycols 350, 550, 750, 2000, 5000, poly(ethylene        oxide) homopolymers (100,000-5,000,000), polyalkylene glycols        and derivatives, hexylene glycol (2-methyl-2,4-pentanediol),        1,3-butylene glycol, 1,2,6-hexanetriol, ethohexadiol USP        (2-ethyl-1,3-hexanediol), and polyoxypropylene derivatives of        trimethylolpropane are suitable examples.    -   XIV. Polyhydric alcohol esters. Mono- and di-acyl esters of        ethylene glycol, mono- and di-acyl esters of diethylene glycol,        mono- and di-acyl esters of polyethylene glycol (200-6000),        mono- and di-acyl esters of propylene glycol, polypropylene        glycol 2000 monooleate, polypropylene glycol 2000 monostearate,        ethoxylated propylene glycol monostearate, mono- and di-acyl        esters of glycerol, poly-acyl esters of poly glycerol,        ethoxylated glycerol monostearate, 1,3-butylene glycol        monostearate, 1,3-butylene glycol distearate, acyl ester of        polyoxyethylene polyol, acyl esters of sorbitan, and acyl esters        of polyoxyethylene sorbitan are suitable examples.    -   XV. Waxes such as beeswax, spermaceti, myristoyl myristate and        stearyl stearate.    -   XVI. Beeswax derivatives, such as polyoxyethylene sorbitol        beeswax. These are reaction products of beeswax with ethoxylated        sorbitol of varying ethylene oxide content that form a mixture        of ether-esters.    -   XVII. Vegetable waxes, including, but not limited to, carnauba        and candelilla waxes.    -   XVIII. Phospholipids such as lecithin and derivatives.    -   XIX. Sterols. Examples include, but are not limited to,        cholesterol and acyl esters of cholesterol.    -   XX. Amides, such as fatty acid amides, ethoxylated acyl amides        and solid fatty acid alkanolamides.

The lotions of the invention would further contain from 1% to 30% of anemulsifier. The emulsifiers can be anionic, cationic or non-ionic.Examples of non-ionic emulsifiers include, but are not limited to, fattyalcohols having 10 to 20 carbon atoms, fatty alcohols having 10 to 20carbon atoms condensed with 2 to 20 moles of ethylene oxide or propyleneoxide, alkyl phenols with 6 to 12 carbons in the alkyl chain condensedwith 2 to 20 moles of ethylene oxide, mono- and di-acyl esters ofethylene glycol, wherein the fatty acid contains from 10 to 20 carbons,monoglycerides wherein the fatty acid contains from 10 to 20 carbons,diethylene glycol, polyethylene glycols of molecular weight 200 to 6000,polypropylene glycol of molecular weight 200 to 3000, glycerol,sorbitol, sorbitan, polyoxyethylene sorbitol, polyoxyethylene sorbitanand hydrophilic wax esters. Suitable anionic emulsifiers include, butare not limited to, fatty acids saponified (soaps) with potassium,sodium, or triethanolamine, wherein the fatty acid contains from 10 to20 carbons. Other suitable anionic emulsifiers include, but are notlimited to, alkali metals, ammonium or substituted ammonium with alkylsulfates, alkyl arylsulfonates and alkyl ethoxy ether sulfonates having10 to 30 carbons in the alkyl chain and from 1 to 50 ethylene oxideunits. Suitable cationic emulsifiers include quaternary ammonium andmorpholinium and pyridinium compounds.

Some emollients previously described also have emulsifying properties.When a lotion contains one of these emollients, an additional emulsifieris not needed, though it can be included in the formulation.

The balance of the composition is water. The lotions are formulated bysimply admixing all of the components together. Preferably, thecompounds of Formula I are dissolved in the emollient and the resultingmixture is added into the water. Optional components such as theemulsifier or common additives may be included in the composition. Acommon additive is a thickening agent included at a level of 1% to 30%by weight of the composition. Examples of suitable thickening agentsare: Cross-linked carboxypolymethylene polymers, methyl cellulose,polyethylene glycols, gums and bentonite.

Creams

The compositions of the present invention may be also formulated in theform of a cream. Creams contain from 0.001% to 30% of the inventivecompounds of Formula (I), from 5% to 50% of an emollient and theremainder is water. The emollients, as described above, can also be usedin the cream formulation. Optionally, the cream may contain anemulsifier at a level from 3% to 50%. The previously describedemulsifiers would also be adequate in this case.

Solutions

The compositions of the present invention may also be formulated in theform of a solution. Solutions contain from 0.001% to 30% of theinventive compounds: of Formula (I), and the adequate amount of anorganic solvent. Organic substances useful as the solvent or a part ofthe solvent system are as follows: propylene glycol, polyethylene glycol(200-600), polypropylene glycol (425-2025), glycerine, sorbitol esters,1,2,6-hexanetriol, ethanol, isopropanol, diethyl tartrate, butanediol,and mixtures thereof. Such solvent systems can also contain water. Thesecompositions are applied on the skin in the form of a solution, orsolutions are formulated in the form of aerosol and applied on the skinas a spray. Compositions in the form of aerosol additionally containfrom 25% to 80% of a suitable propellant. Examples of propellantsinclude, but are not limited to: chlorinated, fluorinated andfluorochlorinated low molecular weight hydrocarbons. Nitrous oxide andcarbon dioxide are also used as propellant gases. Enough quantity toexpel the content of the cartridge is used.

Gels

The composition in the form of gel might be simply obtained by theaddition of a suitable thickening agent to the composition in the formof a solution as described above. Suitable thickening agents have beendescribed in the chapter referring to lotions.

Gel formulations contain from about 0.001% to about 30% of the compoundsof Formula (I), 5% to 75% of a suitable organic solvent, 0.5% to 20% ofa suitable thickening agent and the required amount of water.

Solids

The compositions in the present invention may also be formulated insolid form. Such forms have the shape of a bar intended for theapplication on the lips or other parts of the body. These compositionscontain from about 0.001% to about 30% of the inventive compounds: ofFormula (I), and from about 50% to about 98% of an emollient such as theone already described. The composition may be further contain from about1% to about 20% of a suitable thickening agent, such as those alreadydescribed, and, optionally, emulsifiers and water.

Additives usually found in topical compositions, such as preservatives(for example, methyl and ethyl paraben), dyes and perfumes may beincluded in any of the formulations described herein.

Application Method

The effective amount of compounds of Formula (I) used topically willvary according to the specific circumstances of application, theduration of exposure and similar considerations. Generally, the amountwill vary from 0.01 microgram to 50 milligrams of the compounds ofFormula (I), per square centimeter of the epidermis area. The amount oftopical composition (the compounds of Formula (I) and the vehicle)applied on the affected area may be easily determined according to theamount of compounds of Formula (I) contained therein.

Kits

In yet other embodiments, the invention provides a kit or packagecomprising a compound of formula (I), in packaged form, accompanied byinstructions for use. The compound of formula (I) may be packaged in anymanner suitable for administration, so long as the packaging, whenconsidered along with the instructions for administration, indicates themanner in which the compound of formula (I) is to be administered.

For example, a kit may comprise a compound of formula (I) in unit dosageform, along with instructions for use. For example, such instructionsmay indicate that administration of a compound of formula (I) is usefulin the treatment of actinic keratosis. The compound of formula (I) maybe packaged in any manner suitable for administration. For example, whenthe compound of formula (I) is in oral dosage form, e.g., is in the formof a coated tablet, then the kit may comprise a sealed container ofcoated tablets, blister strips containing the tablets, or the like.

Various embodiments according to the above may be readily envisioned,and would depend upon the particular dosage form, recommended dosage,intended patient population, and the like. The packaging may be in anyform commonly employed for the packaging of pharmaceuticals, and mayutilize any of a number of features such as different colors, wrapping,tamper-resistant packaging, blister packs or strips, and the like.

The following non-limiting examples further describe and enable one ofordinary skill in the art to make and use the present invention.

EXAMPLES Example 1 Assay of 2,5-dihydroxybenzenesulfonic Acid onPhotoaged Skin

In this study, 2,5-dihydroxybenzenesulfonic acid, potassium salt,formulated as 5% by weight in the form of cream has been used, sincethis type of formulation is a habitual procedure for topical treatmentsof the skin. Distilled water has been used as the aqueous phase of thecream. The oil phase thereof may comprise cetyl alcohol, stearyl alcoholor vaseline. Span (sorbitan monooleate) is an effective emulsifier tomake the cream.

The following example illustrates the formulation of an effective creamfor the topical treatment of skin photoaging and must not be construedas a limitation of the scope of the invention.

Active principle: 2,5-dihydroxybenzenesulfonic acid, potassium salt, 5%by weight. Excipients: cetyl alcohol (2.5%), stearyl alcohol (2.5%),liquid vaseline (30%), white soft vaseline (20%), sorbitan monooleate(5%) and distilled water (q.s. to 100 g).

Continuous topical treatment of human photoaged skin with this cream(twice a day for 3 months) (FIG. 1A) results in a reduction of thewrinkles and the disappearance of actinic lentigo areas, as shown inFIG. 1B. Lightening of skin hyperpigmentation after the application of2,5-dihydroxybenzenesulfonic acid may justify the use thereof to treatmelanic dyschromia with hyperpigmentation as occurs, among otherpathologies, in the Mongolian spot, the nevus of Ota, the nevus of Ito,the nevus of Becker, ephelides (freckles), the lentigo malign melanoma,the café-au-lait macules or the melasma (chloasma).

Example 2 Effect of 2,5-dihydroxybenzenesulfonate on SeborrheicKeratosis, Actinic Keratosis and Viral Warts

Topical treatment with the above described cream (twice a day for 11days) of human skin (basal conditions shown in FIG. 2A) results in areduction of seborrheic keratosis (big circle) as well as of viral warts(small circle), as shown in FIG. 2B.

Another example of the effect of 2,5-dihydroxybenzenesulfonate onseborrheic keratosis is shown in FIG. 3, wherein the seborrheickeratosis is reduced due to the topical treatment on the affected areafor 4 weeks, twice a day, with an emulsion containing the2,5-dihydroxybenzenesulfonic acid, 2.5% by weight.

The emulsion containing 2.5% by weight of 2,5-dihydroxybenzenesulfonicacid was also used to treat two lesions of actinic keratosis in the samepatient, as shown in FIGS. 4 and 5. After 15 days of treatment with saidemulsion (twice a day), the actinic keratosis was clearly reduced, andthe effect was even more evident after 4 weeks of treatment.

Example 3 Effect of an Emulsion of 2.5% 2,5-dihydroxybenzenesulfonate onActinic Keratosis

An emulsion containing 2.5% by weight of 2,5-dihydroxybenzenesulfonicacid was used to treat two lesions of actinic keratosis in the samepatient, as shown in FIGS. 4 and 5. After 15 days of treatment with saidemulsion (twice a day), the actinic keratosis was clearly reduced, andthe effect was even more evident after 4 weeks of treatment. Calciumsalt of 2,5-dihydroxybenzenesulfonic acid was used.

Example 4 Effect of a Cream of 5% 2,5-dihydroxybenzenesulfonate onActinic Keratosis

In this study, 2,5-dihydroxybenzenesulfonic acid, potassium salt,formulated as 5% by weight in the form of cream has been used, sincethis type of formulation is a habitual procedure for topical treatmentsof the skin. Distilled water has been used as the aqueous phase of thecream. The oil phase thereof may comprise cetyl alcohol, stearyl alcoholor vaseline. Span (sorbitan monooleate) is an effective emulsifier tomake the cream.

The following example illustrates the formulation of an effective creamfor the topical treatment of skin photoaging and must not be construedas a limitation of the scope of the invention.

Active principle: 2,5-dihydroxybenzenesulfonic acid, potassium salt, 5%by weight.

Excipients: cetyl alcohol (2.5%), stearyl alcohol (2.5%), liquidvaseline (30%), white soft vaseline (20%), sorbitan monooleate (5%) anddistilled water (q.s. to 100 g).

The mentioned formulation was topically applied to actinic keratosislesions in two different patients, demonstrating the efficacy of thecream containing 5% 2,5-dihydroxybenzenesulfonate to treat actinickeratosis (FIGS. 6 and 7).

Example 5 Effect of 2,5-dihydroxybenzenesulfonic Acid on Hair Growth

2,5-dihydroxybenzenesulfonic acid, potassium salt, formulated in theform of cream was used and its composition was the same as that used inexample 1.

As shown in FIG. 8B, the continuous topical treatment with this cream(twice a day for 3 months) results in the disappearance of hair in thearea of application.

Example 6 Effect of the 2,5-dihydroxybenzenesulfonic Acid on SolarLentigos

The 2,5-dihydroxybenzenesulfonic (DHBS; 5%) cream described in example 1was used for the topical treatment of solar lentigos in a patient. Asshown in FIG. 9, after a two week treatment with DHBS in the form ofcream there is a reversal of the solar lentigos.

Example 7 Assay of the 2,5-dihydroxybenzenesulfonic Acid forAdipogenesis

In order to demonstrate the new antiadipogenic mechanism of2,5-dihydroxybenzenesulfonic acid we have used the cell line ofpreadipocytes 3T3L1. The preadipocytes were seeded in a 6 well platewhere they grew up to the confluence In a standard culture medium[Dulbecco's Essential Medium (DEM)], supplemented with 1.5 g/L of sodiumbicarbonate, non essential aminoacids and 10% bovine fetal serum.2,5-dihydroxybenzenesulfonic acid (25 μM) was added to the culturemedium of three wells. The culture medium was renewed every two days.After seven days, the differentiation to adipocytes was initiated in thesix wells by the addition of dexametasone (250 μM),3-isobutyl-1-methylxanthine (0.5 mM) and insuline (160 nM) during twodays, followed by the substitution of the culture medium by anotherculture medium containing insuline (160 nM) during five days. Thetreatment with 2,5-dihydroxybenzenesulfonic acid (25 μM) was maintainedin three wells. The culture medium was renewed every two days.

12 days later, the adipogenesis was determined by staining with Oil RedO to check the cytoplasmic accumulation of triglycerides. The cells werewashed with phosphate buffer (PBS), fixed with 4% paraformaldehyde andstained during thirty minutes with Oil Red O. Isopropanol was used toremove the dye from the cells to quantify the accumulation of lipids;the absorbance thereof was measured at 510 nm in a spectrophotometer.

When 3T3-L1 cells (preadipocytes) are treated with2,5-dihydroxybenzenesulfonic acid (25 μM) during 12 hours, there is avery significant reduction in the number of preadipocytes differentiatedin adipocytes, as shown in FIG. 10. FIG. 10A corresponds to a controlculture wherein most of the cells are adipocytes containing triglyceridedeposits. FIG. 10B shows a culture treated with2,5-dihydroxybenzenesulfonic acid. Most of these cells exhibit anon-differentiated (pre-adipocytes) aspect with scarce accumulation oftriglycerides in the cytoplasm. FIG. 11 represents an histogramcorresponding to the quantification of triglycerides(spectrophotometrically identified by the Oil Red O absorbance) in threecontrol cultures and in three cultures treated with the2,5-dihydroxybenzensulfonic compound.

This example evidences that the 2,5-dihydroxybenzene derivativessignificantly inhibit adipogenesis.

Example 8 Assay of 2,5-dihydroxybenzoic Acid for Adipogenesis

Following the same methodology explained in example 7, the effect of thegentisic acid (2,5-dihydroxybenzoic; 50 μM) was evaluated over thedifferentiation of the preadipocytes and the adipogenesis. In FIG. 12,the photo on the left is the control culture and the one on the rightshows the 3T3-L1 preadipocytes treated with gentisic acid during twoweeks. The gentisic acid inhibits the differentiation of thepreadipocytes and the adipogenesis.

In FIG. 13, the quantification of triglycerides (spectrophotometricallyidentified by the absorbance of Oil Red O) clearly demonstrates that thegentisic acid inhibits the differentiation of preadipocytes toadipocytes as well as the adipogenesis since it avoids the accumulationof lipids in the cells.

Example 9 Inhibition of the Proliferation of Preadipocytes ofSubcutaneous Fat

In the adipogenesis, besides the differentiation capacity of thepreadipocytes in the cells capable of storing lipids, also matters theproliferative capacity of the preadipocytes before converting intodifferentiated cells. Therefore, we assessed the effect ofhydroxybenzene derivatives on rabbit subcutaneous fat preadipocyteproliferation was assessed.

The primary cultures of rabbit preadipocytes were obtained from theinguinal fat of New Zealand rabbits. Once the fat is removed, it isprocessed by mechanical disaggregation and enzymatic digestion with0.075% type I collagenase (Gibco BRL, Paisley, Scotland, RU) for 30minutes at 37°. The mature adipocytes are separated, removed bycentrifugation (300×g, 5 min) and the cell sediment is selected. Then,the mononuclear cells with low cell density are isolated by densitygradient centrifugation with Ficoll-Paque (Amersham Biosciences,Uppsala, Sweden). Once the low density mononuclear cells are obtained,they are seeded in a 75 cm² culture flask and cultured in an incubatorat 37° C. with air containing 5% CO₂, in an Eagle medium modified byDulbecco (DMEM) (Gibco) with 10% of bovine fetal serum (Gibco) and 0.1%of antibiotic-antimicotic (Gibco). The culture medium is replaced 24hours later to remove the cells present in the supernatant, and toselect the cells adhered to the culture flask. Then, the medium ischanged every 4 days until de culture grows up to 70-80% confluence; atthat moment the cells are taken off with 0.05% (w/w) trypsin (Sigma) inHank's balanced salt solution (HBSS) (Sigma), to obtain subcultures forcell expansion. Once the subcultures reach passages 2-3, they are usedto carry out experiments or they are frozen in aliquots of liquidnitrogen for later use.

The rabbit preadipocytes proliferation experiments were carried out in24-well plates. Por this purpose, 2×10⁴ cells were seeded per well andthey were treated with vehicle, 2,5-dihydroxybenzenesulfonic (DHBS; 10to 100 μM) or 2-acetoxy-5-hydroxybenzenesulfonic (2A-5HBS; 10 to 500μM). The proliferation of preadipocytes was evaluated 72 hours later,and at that moment the cells were fixed with 1% glutaraldehyde. Thecellular proliferation was evaluated using the crystal violet method, bymeasuring the absorbance at a wave length of 595 nm.

The DHBS and 2A-5HBS significantly inhibited the proliferation ofpreadipocytes obtained from subcutaneous fat of the rabbit (FIGS. 14 and15). The effects were dependent on the concentration, obtaining asignificant effect as of 50 μM for DHBS (FIG. 14) and as of 100 μM for2A-5HBS (FIG. 15).

Surprisingly, as the following examples illustrate, in addition to FIG.15 of example 9, in certain embodiments, the esters of2,5-dihydroxybenzene sulfonate described in the present invention exertpharmacological actions of interest in the present invention bythemselves, without needing to be first converted into2,5-dihydroxybenzenesulfonate in order to exert such actions.

Example 10 Inhibition of Fibroblasts Mitogenesis Induced by theFibroblast Growth Factor-1 (FGF-1)

Inhibition of FGF-1 mitogenesis was observed in quiescent cultures ofBalb/c 3T3 fibroblasts by 2-acetoxy-5-hydroxybenzenesulfonate (FIG. 16),5-acetoxy-2-hydroxybenzenesulfonate (FIG. 17) and2,5-diacetoxybenzenesulfonate (FIG. 18). The evaluated compounds wereused in the form of potassium salt, except in the first case in whichcalcium salt was used. The experiments were carried out as described inFernández-Tornero C et al. J Biol Chem, 2003.

Example 11 Effect of Monoesters of 2,5-dihydroxybenzenesulfonate on theProliferation of Mouse Glioma C6 Cells

The following example shows the efficacy of the monoesters of2,5-dihydroxybenzenesulfonic, potassium2-acetoxy-5-hydroxybenzenesulfonate (2A-5HBS) and potassium5-acetoxy-2-hydroxybenzenesulfonate (5A-2HBS) to reduce theproliferation capacity of glioma cells and supports the use of thecompounds in the treatment of gliomas.

The cell line used was that of mouse glioma C6 cells. Once attached, thecells were treated o not treated (controls) with (5A-2HBS) (500 μM) or(2A-5HBS) (500 μM) and they were allowed to proliferate during 48 hours.After that, the proliferation of glioma cells was evaluated by stainingthe fixed cells with crystal violet. The number of cells is proportionalto the amount of retained dye, which was spectrophotometricallydetermined by measuring absorbance at 595 nm after removing the dye fromthe cells.

Both monoesters of 2,5-dihydroxybenzenesulfonate, (5A-2HBS) and(2A-5HBS) caused the inhibition of the proliferation of mouse gliomacells (FIG. 19).

Example 12 Analysis of the Structural Interaction of the Esters of2,5-dihydroxybenzenesulfonate with the Fibroblast Growth Factor-1(FGF-1)

As of the diffraction from complex crystals of FGF-1:2-acetoxy-5-hydroxybenzenesulfonic acid, FGF-1:5-acetoxy-2-hydroxybenzenesulfonic acid and FGF-1:2,5-diacetoxybenzenesulfonic acid, the complex structures werecalculated and represented. In FIGS. 20, 21 and 22, representing thesurface of the protein cloured according to its electrostatic potential(light grey: negative charge, dark grey: positive charge, white: areaswith no charge), the interaction form of the2-acetoxy-5-hydroxybenzenesulfonic acid,5-acetoxy-2-hydroxybenzenesulfonic acid and 2,5-diacetoxybenzenesulfonicacid, respectively, with the FGF-1 may be observed. The electronicdensity of the compound, contoured at 1σ (FIGS. 20-22, panels C),enabled the localization and determination of the orientations of thecompounds regarding the protein (FIGS. 20-22, panels A and B), as wellas the confirmation that the compounds keep the acetoxyl groups inpositions 2, 5 and, 2 and 5, respectively, when they bind to theprotein. The compounds are located at a site very close to the sitethat, as described, is occupied by the 2,5-dihydroxybenzenesulfonicacid, which aromatic ring forms a cation-π bond with the N^(ε) group oflysine 132, marked in FIGS. 20-22, panels A, as reference.

Each patent, patent application, and publication cited or described inthe present application is hereby incorporated by reference in itsentirety as if each individual patent, patent application, orpublication was specifically and individually indicated to beincoporated by reference.

While specific embodiments of the subject invention have been discussed,the above specification is illustrative and not restrictive. One skilledin the art will appreciate that numerous changes and modifications canbe made to the invention, and that such changes and modifications can bemade without departing from the spirit and scope of the invention. Thefull scope of the invention should be determined by reference to theclaims, along with their full scope of equivalents, and thespecification, along with such variations.

1. A method for the treatment or prophylaxis of actinic keratosis,comprising administering to a subject in need thereof, an effectiveamount of a 2,5-dihydroxybenzene derivative represented by Formula (I)or a pharmaceutically acceptable salt, solvate, isomer, or prodrugthereof, wherein the compound of Formula (I) is:

wherein: R₁ is —(CH₂)_(a)Y or —CH═CH—(CH₂)_(p)Y; Y is —SO₃H, —SO₃ ⁻.X⁺,—SO₃R₃, —PO₃H, —PO₃—.X⁺, —PO₃R₃, —CO₂H, —CO₂ ⁻.X⁺ or —CO₂R₃; X⁺ is anorganic cation or an inorganic cation, such that the general charge ofthe compound of Formula (I) is neutral; R₉ and R_(9′) are independentlyselected from —OH and —OR₂, wherein when R₉ and R_(9′) are both —OR₂,then said R₉ and R_(9′) can be the same or different; R₂ is asubstituted or unsubstituted alkyl group, a substituted or unsubstitutedaryl group, a substituted or unsubstituted alkylsulfonyl group, asubstituted or unsubstituted arylsulfonyl group, a substituted orunsubstituted alkylcarbonyl group or a substituted or unsubstitutedarylcarbonyl group; R₃ is a substituted or unsubstituted alkyl group ora substituted or unsubstituted aryl group; a is a number selected from0, 1, 2, 3, 4, 5 and 6; and p is a number selected from 0, 1, 2, 3, 4, 5and
 6. 2. The method of claim 1, wherein Y is selected from —SO₃H, —SO₃⁻.X, —SO₃R₃, —CO₂H, —CO₂ ⁻.X⁺ and —CO₂R₃.
 3. The method of claim 1 orclaim 2, wherein at least one of R₉ and R_(9′) are, independently, asubstituted or unsubstituted alkylsulfonyloxy group, a substituted orunsubstituted arylsulfonyloxy group, a substituted or unsubstitutedalkylcarbonyloxy group or a substituted or unsubstituted arylcarbonyloxygroup
 4. The method of claim 2, wherein R₂ is selected frommethylcarbonyl, phenylsulfonyl, 4-methylphenylsulfonyl, benzylsulfonyl,benzyl and phenyl.
 5. The method of claim 1, wherein the compound ofFormula (I) is selected from the group consisting of:2,5-dihydroxybenzenesulfonic acid (Dobesilate),5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;2-(acetyloxy)-5-hydroxybenzenesulfonic acid;5-(acetyloxy)-2-hydroxybenzenesulfonic acid;2,5-bis(acetyloxy)benzenesulfonic acid;2-(benzyloxy)-5-hydroxybenzenesulfonic acid;5-(benzyloxy)-2-hydroxybenzenesulfonic acid;2,5-bis(benzyloxy)benzenesulfonic acid; 2,5-dihydroxybenzenehomosulfonic acid (homodobesilate)5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;2-(acetyloxy)-5-hydroxybenzenehomosulfonic acid;5-(acetyloxy)-2-hydroxybenzenehomosulfonic acid;2,5-bis(acetyloxy)benzenehomosulfonic acid;2-(benzyloxy)-5-hydroxybenzenehomosulfonic acid;5-(benzyloxy)-2-hydroxybenzenehomosulfonic acid;2,5-bis(benzyloxy)benzenehomosulfonic acid; 2,5-dihydroxybenzoic acid(gentisic acid), 5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzoicacid; 2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzoic acid;2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzoic acid;2-(acetyloxy)-5-hydroxybenzoic acid; 5-(acetyloxy)-2-hydroxybenzoicacid; 2,5-bis(acetyloxy)benzoic acid; 2-(benzyloxy)-5-hydroxybenzoicacid; 5-(benzyloxy)-2-hydroxybenzoic acid; 2,5-bis(benzyloxy)benzoicacid; 2,5-dihydroxyhomobenzoic acid (homogentisic acid),5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid;2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid;2,5-bis{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid;2-(acetyloxy)-5-hydroxyhomobenzoic acid;5-(acetyloxy)-2-hydroxyhomobenzoic acid; 2,5-bis(acetyloxy)homobenzoicacid; 2-(benzyloxy)-5-hydroxyhomobenzoic acid;5-(benzyloxy)-2-hydroxyhomobenzoic acid; 2,5-bis(benzyloxy)homobenzoicacid; 3-(2,5-dihydroxyphenyl)-2-propenoic acid (2,5-dihydroxycinnamicacid) 3-(5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoicacid; 3-(2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoicacid; 3-(2,5-bis{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic acid;3-(2-(acetyloxy)-5-hydroxyphenyl)-2-propenioc acid;3-(5-(acetyloxy)-2-hydroxyphenyl)-2-propenoic acid;3-(2,5-bis(acetyloxy)phenyl)-2-propenoic acid;3-(2-(benzyloxy)-5-hydroxyphenyl)-2-propenoic acid;3-(5-(benzyloxy)-2-hydroxyphenyl)-2-propenoic acid;3-(2,5-bis(benzyloxy)phenyl)-2-propenoic acid; and pharmaceuticallyacceptable salts, solvates and prodrugs thereof.
 6. The method of claim5, wherein the compound of Formula (I) comprises an ester at position 1.7. The method of claim 5, wherein the compound of Formula (I) isselected from: 2-(acetyloxy)-5-hydroxybenzenesulfonic acid;5-(acetyloxy)-2-hydroxybenzenesulfonic acid and2,5-bis(acetyloxy)benzenesulfonic acid.
 8. The method of claim 5,wherein the compound of Formula (I) is selected from the groupconsisting of: calcium 2,5-dihydroxybenzenesulfonate (calciumDobesilate); potassium 2,5-dihydroxybenzenesulfonate (potassiumDobesilate); magnesium 2,5-dihydroxybenzenesulfonate (magnesiumDobesilate); diethylamine 2,5-dihydroxybenzenesulfonate (Ethamsylate);9. The method of claim 8, wherein the compound of Formula (I) is calcium2,5-dihydroxybenzenesulfonate (calcium Dobesilate).
 10. The method ofclaim 8, wherein the compound of Formula (I) is potassium2,5-dihydroxybenzenesulfonate (potassium Dobesilate).
 11. The method ofclaim 1, wherein the actinic keratosis is selected from the groupconsisting of: hypertrophic, atrophic, bowenoid, and acantholythickeratosis.
 12. The method of claim 1, wherein the compound of Formula(I) is administered topically.
 13. The method of claim 12, wherein thecompound of Formula (I) is administered orally, buccally, transdermally,by inhalation, rectally, intravaginally, or optically.
 14. The method ofclaim 1, further comprising administration of at least one additionaltherapeutic agent.
 15. The method of claim 14, wherein the at least oneadditional therapeutic agent is selected from the group consisting of:imiquimod, diclofenac, glycidic acid, trichloroacetic acid, colchicine,T4 endonuclease, 5-fluorouracil, isotretinoin, acitretin, cidofoir,5-aminolevulinic acid, methyl aminolevulinate, hypericin,chemotherapeutic agent, a corticosteroid, an antibiotic, an analgesic,an immunomodulator, an immunosuppressant, an anti-angiogenic, aleukotriene modifier, an aminosalicylate, an anesthetic, a non-steroidalanti-inflammatory, a modifier of a solubilized interleukin receptor, acytotoxic, an inhibitor of a tyrosine-kinase receptor, a protein kinaseC inhibitor, and combinations of two or more thereof.
 16. The method ofclaim 1, further comprising at least one coadjuvant therapy selectedfrom the group consisting of: photodynamic therapy, cryotherapy,curettage, and surgery.
 17. The method of claim 12, wherein the compoundis administered at least once per week.
 18. The method of claim 17,wherein the compound is administered at least once per day.
 19. Themethod of claim 18, wherein the compound is administered at least twiceper day.
 20. The method of claim 12, wherein the compound is present ina pharmaceutical composition in an amount of at least about 1% w/w. 21.The method of claim 20, wherein the compound is present in apharmaceutical composition in an amount of at least about 2.5% w/w. 22.The method of claim 21, wherein the compound is present in apharmaceutical composition in an amount of at least about 5% w/w. 23.The method of claim 22, wherein the compound is present in apharmaceutical composition in an amount of at least about 10% w/w. 24.The method of claim 23, wherein the compound is present in apharmaceutical composition in an amount of at least about 15% w/w. 25.The method of claim 12, wherein the compound is administered over aperiod of at least about one week.
 26. The method of claim 25, whereinthe compound is administered over a period of at least about four weeks.